This invention relates to methods of building bone in humans and other animals, i.e., for the treatment of osteoporosis and related disorders. In particular, this invention relates to such methods of treatment by administration of opioids, opioid-degrading enzyme inhibitors, enkephalin secretagogues, or mixtures thereof.
The most common metabolic bone disorder is osteoporosis. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. In general, there are two types of osteoporosis: primary and secondary. "Secondary osteoporosis" is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases is "primary osteoporosis". Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.
For some osteoporotic individuals the loss of bone tissue is sufficiently great so as to cause mechanical failure of the bone structure. Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
The mechanism of bone loss in osteoporotics is believed to involve an imbalance in the process of "bone remodeling". Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. Th is remodeling involves the erosion and filling of discrete sites on the surface of bones, by an organized group of cells called "basic multicellular units" or "BMUs". BMUs primarily consist of "osteoclasts", "osteoblasts", and their cellular precursors. In the remodeling cycle, bone is resorbed at the site of an "activated" BMU by an osteoclast, forming a resorption cavity. This cavity is then filled with bone by an osteoblast.
Normally, in adults, the remodeling cycle results in a small deficit in bone, due to incomplete filling of the resorption cavity. Thus, even in healthy adults, age-related bone loss occurs. However, in osteoporotics, there is an increase in the number of BMUs that are activated. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss.
Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium intake, physical inactivity, and estrogen deficiency.
Many compositions and methods are described in the medical literature for the "treatment" of osteoporosis. Many of these compositions and methods attempt to either slow the loss of bone or to produce a net gain in bone mass. See, for example, R. C. Haynes, Jr. et al., "Agents Affecting Calcification", The Pharmacological Basis of Therapeutics, 7th Edition (A. G. Gilman, L. S. Goodman et al., Editors, 1985); G. D. Whedon et al., "An Analysis of Current Concepts and Research Interest in Osteoporosis", Current Advances in Skeletogenesis (A. Ornoy et al., Editors, 1985); and W. A. Peck, et al., Physician's Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Foundation.
Among the treatments for osteoporosis suggested in the literature is the administration of bisphosphonates or other bone-active phosphonates. See, for example, Storm et al., "Effect of Intermittent Cyclical Etidronate Therapy on Bone Mineralization and Fracture Rate in Women with Post-Menopausal Osteoporosis", 322 New England Journal of Medicine 1265 (1990); and Watts et al., "Intermittent Cyclical Etidronate Treatment of Post-Menopausal Osteoporosis", 323 New England Journal of Medicine 73 (1990). Such treatments using a variety of bisphosphonates are described in, for example, U.S. Pat. No. 4,761,406, Flora et al., issued Aug. 2, 1988; U.S. Pat. No. 4,812,304, Anderson et al., issued Mar. 14, 1989; U.S. Pat. No. 4,812,311, Uchtman, issued Mar. 14, 1989; and U.S. Pat. No. 4,822,609, Flora, issued Apr. 18, 1989. The use of such phosphonates for the treatment of osteoporosis, and other disorders involving abnormal calcium and phosphate metabolism, is also described in U.S. Pat. No. 3,683,080, Francis, issued Aug. 8, 1972; U.S. Pat. No. 4,330,537, Francis, issued Oct. 28, 1980; U.S. Pat. No. 4,267,108, Blum et al., issued May 12, 1981; European Patent Publication 298,553, Ebetino, published Jan. 11, 1989; and Francis et al., "Chemical, Biochemical, and Medicinal Properties of the Diphosphonates", The Role of Phosphonates in Living Systems 55 (1983).
Administration of estrogen is also used as a means to prevent osteoporosis in postmenopausal women. This therapy typically involves daily administration of from about 0.625 milligrams to about 1.25 milligrams of conjugated estrogens, or equivalent amounts of other estrogen hormones. Estrogen may also be used to treat osteoporosis, although this has not been fully established. See, for example, Barzel, "Estrogens in the Prevention and Treatment of Post-Menopausal Osteoporosis: Is it Effective?" Hospital Practice 95 (1990); Ettinger, et al., "Post-Menopausal Bone Loss is Prevented by Treatment with Low-Dosage Estrogen with Calcium", 106 Annals in Internal Medicine 40 (1987); Lindsay, et al., "The Minimum Effective Dose of Estrogen for Prevention of Post-Menopausal Bone Loss", 63 Obstetrics and Gynecology 759 (1984); and "Estrogen", Drug Information 1765 (1990).
While estrogen may be useful in preventing (and, potentially treating) osteoporosis and other bone metabolism disorders, the use of estrogen has been associated with certain side effects, such as uterine bleeding. See, Rudy, "Hormone Replacement Therapy--How to Select the Best Preparation and Regimen," 88 Postgraduate Medicine 157 (1990). In addition, long-term estrogen therapy has been linked to an increased risk of endometrial carcinoma and inflammatory gallbladder disease. See Id.
In spite of the many compositions and methods described in the art, there is a continuing need for new safe and effective methods of treating bone metabolism disorders. As indicated, there are potential side effects associated with estrogen therapy. Similarly, phosphonate therapy (particularly bisphosphonate therapy) may result in certain side effects. For example, bisphosphonates are known to prevent bone loss by inhibiting bone resorption. Because bone resorption is coupled with bone formation, bisphosphonates generally inhibit the rate of bone formation.
It is therefore an object of the present invention to provide methods useful in treating osteoporosis and related disorders. Applicants have found that, surprisingly, osteoporosis may be treated by administering opioids, opioid-degrading enzyme inhibitors, enkephalin secretagogues, or mixtures thereof.